GB2233331A

GB2233331A - Substituted 1,3- diaminopropanes

Info

Publication number: GB2233331A
Application number: GB9014245A
Authority: GB
Inventors: Robin Gerald Shepherd
Original assignee: John Wyeth and Brother Ltd
Current assignee: John Wyeth and Brother Ltd
Priority date: 1989-06-30
Filing date: 1990-06-27
Publication date: 1991-01-09
Also published as: GB8915131D0; EP0405932A3; JPH0344360A; IE902377L; IE902377A1; GB9014245D0; US5010196A; EP0405932A2; CA2020189A1; KR910000621A

Description

1 J This invention relates to a process for preparing substituted 1,3-

diaminopropanes and to intermediates useful in the process. In particular the invention relates to a process for selectively acylating N-alkyl5 1,3diaminopropanes to give W-acyl-N-alkyl-1,3diaminopropanes. In this specification -acyl- is to be understood to include both hydrocarbon acyl groups of the type RCO- and aminoacyl groups of the type RNHCO(where R is a substituted or unsubstituted hydrocarbon

group such as a substituted or unsubstituted alkyl or aryl group). "Acylating' is used in a similar manner as relating to the introduction of both types of "acyl" groups.

A number of N'-acyl-N-alkyl-1,3-diaminopropanes are described in the literature; compounds in which the acyl group is an aminoacyl group have been described as being useful as pharmaceuticals. For example, German Patent specification 1038031 discloses certain Naminoalkyl-N'-(2-chloro-6-methylphenyl)-ureas as local anaesthetics. the formula GB 2025406B discloses compounds of Y-NH.COMCH 2 CH 2 CH 2NH-X (wherein Y is 2,6-dimethylphenyl, 2,5-dimethylphenyl, 5-bromo-2methylphenyl or 5-chloro-2-methylphenyl. and X is propyl, isopropyl, nbutyl or isobutyl) as being useful as anti-arrhythmic agents. A preferred compound is recainam which is the compound of the above formula in which Y is 2,6-dimethylphenyl and X is isopropyl.

The described processes for preparing the N'acyl-N-alkyl-3-diaminopropanes have disadvantages especially when used on a commercial scale. For H-400f example reaction of an acylating agent with an N-alkyl1,3-diaminopropane can give a mixture of products since the acylating agent can acylate either the primary or secondary amino group. GB 2025406B describes an alternative process in which the primary amino group in the starting material is protected but the yield is still poor because the process comprises a number of separate steps. A third method described in GB 2025406B involves reaction of, for example, a N-(3-chloropropyl)-W-arylurea with an alkylamine. However the yield is poor and an impure product is obtained because of a side reaction in which the alkylamine reacts at the carbonyl group of the urea. A new_process has now been found which gives the desired product by a short route in good yield.

Accordingly the present invention provides a process for preparing a N'acyl-N-alkyl-1,3-diaminopropane of general formula (I) R 1 CONH(CH 2) 3 NHR 2 (I) (where R 1 is R- or R.NH- where R is a substituted or unsubstituted hydrocarbon group and R 2 is alkyl) which comprises reacting a diamine of formula (II) NH 2 (CH 2) 3 NHR 2 (II) (where R 2 has the meaning given above) with an aldehyde 25 of formula (III) R 3 CHO (III) (where R 3 represents hydrogen or lower alkyl to give a hexahydropyrimidine of formula (M H-400f CN-R 2 W7 -" R 3 "-L 1 H (M (where R 2 and R 3 having the meanings given above), acylating the hexahydropyrimidine to give an acylated hexahydropyrimidine of formula (V) ll", N-R 2 C R 3 (V) CO. R (where R 1, R 2 and R 3 have the meanings given above) and hydrolysing the acylated hexahydropyrimidine.

R is preferably a substituted or unsubstituted alkyl or aryl group. The alkyl group may, for example, be lower alkyl. The term "lower" as used herein means that the radical referred to contains 1 to 6 carbon atoms.

Preferably such radicals contain 1 to 4 carbon atoms. Thus the R group may be, fo example, methyl, ethyl, propyl or butyl. When R is an aryl group it is preferably a hydrocarbon aryl group containing 6 to 10 carbon atoms such as phenyl, alkylphenyl or naphthyl.

The alkyl or aryl group may be substituted particularly by one or more substituents common in medicinal chemistry. Such substituents include halogen (for example, fluorine, chlorine, bromine), hydroxy, alkoxy (eg lower alkoxy groups such as methoxy, ethoxy, propoxy, butoxy) amino, monoalkylamino (eg lower alkylamino such as methylamino), dialkylamino (eg diloweralkylamino), acylamino (particularly lower J It H-400f acylamino eg acetamino) and trifluoromethyl. Preferably R 1 represents RNH- and preferably R is a substituted or unsubstituted phenyl group such as those given in the definition of Y above.

R 2 is preferably a lower alkyl group. Examples are given above in connection with the group R. Preferably R 2 is propyl, isopropyl, n-butyl or isobutyl as given in the definition of X above.

The most preferred compound of formula (I) is that in which R 1 represents RNH- where R is 2,6dimethylphenyl and R 2 is isopropyl.

In the process of the invention the diamine of formula (II) is reacted with an aldehyde of formula (III). In formula (III), preferably R3 is hydrogen, ie the aldehyde is formaldehyde. The reaction can be carried out in a solvent. Examples of solvents includes water, lower alkanols and aqueous lower alkanols.

It is not necessary to isolate the hexahydropyrimidine; the reaction product of the diamine and the aldehyde 2 0 can be reacted in situ with an acylating agent in order to acylate the hexahydropyrimidine. When R represents R.NH the acylating agent is preferably an isocyanate, particularly a substituted or unsubstituted aryl isocyanate. When R 1 represents R- the acylating agent may be any of the acylating agents known in the art such as acyl halides, acid anhydrides and the like.

Again it is not necessary to isolate the acylated hexahydropyrimidine. The reaction product of the acylation reaction can be hydrolysed in situ to the desired product. The hydrolysis can be carried out with water although in some instances (particularly H-400f when R 3 is hydrogen) it is preferably to use an aqueous solution of an alkaline metal bisulphite (eg sodium bisulphite) to combine with the aldehyde which is released.

It is an advantage of the process of the present invention that it is not necessary to isolate the intermediates of formula (M and (V) ie the whole process can be carried out in the same reaction vessel.

The products of formula (I) form acid addition salts and can be isolated in the form of the free base or in the form of a pharmaceutically acceptable acid addition salt prepared by reaction of the free base with a pharmaceutically acceptable organic or inorganic acid. Suitable acids will be apparent to those skilled in the art. Examples of such acids are p-toluene sulphonic (tosyl), hydrochloric and phosphoric. The tosyl and hydrochloric salts are generally preferred.

The compounds of formula (V) in which R 1 is RNH- are novel compounds. Accordingly the present invention provides acylated hexahydropyrimidines of formula (Va) CN-R 2 ,,- R 3 N CO. NH. R (Va) where R, R 2 and R 3 have the meanings given above.

H-400f 6- EXAMPLE 1

NisopropylhexahydropyrimL;.d.i..ne.

A solution of N-isopropyl-1,3-propanediamine (116 g, 1M) in isopropyl alcohol (1 1) maintained ca 10 was treated dropwise with 40% aqueous HCHO solution (75 ml, 1M). After 1 hour the solvents were evaporated under reduced pressure and the residue distilled to give Nisopropylhexahydropyrimidine (100 g, 78%), Bp 65'120 mbar.

f 5 EXAMPLE 2

6-Dimethylphenylaminocarbonyl)-3isopropylhexahydropyrimidine 2,6-Dimethylphenylisocyanate (1.5 g) was added dropwise to a solution of Nisopropylhexahydropyrimidine (1.3 g) in acetonitrile (5 ml) (exothermic). After cooling the title compound was isolated by filtration and recrystallised from acetonitrile (2,5 g, 89%), mp 1381390 C.

Found: C, 69.90; H. 9.13; N, 15.26%.

C 16 H 25 N 3 0 requires: C, 69.78; H, 9.15; N, 15.26%.

1 H-400f EXAMPLE 3

N-(2,6-Dimethylphenyl)-W E3-(isopropylamino)propyllurea A solution of 1-(2,6-dimethylphenylaminocarbonyl)- 3-isopropylhexahydropyrimidine (1 g) in methanol (5 ml), saturated aqueous sodium metabisulphate (5 ml), and water (5 ml) was stirred at room temperature for 1 hour. HPLC indicated that complete conversion to recainam. had taken place. The methanol was evaporated under reduced pressure and the product extracted with dichloromethane. The organic phase was dried and evaporated. The residue was dissolved in isopropanol and treated with excess etherial HCl. The product (recainam HCl), (1 g), obtained by filtration and drying in vacuo, was identical with authentic material (i/r, nmr, hplc).

H-400-GB -v

Claims

1. A process for preparing a W-acyl- N-alkyl-1,3-diaminopropane of general formula (I) R 1 CONH(CH 2) 3 NHR 2 (I) (where R 1 is R- or R.NH- where R is a substituted or unsubstituted hydrocarbon group and R2 is alkyl) which comprises reacting a diamine of formula (II) NH 2 (CH 2) 3 NHR 2 (II) (where R 2 has the meaning given above) with an aldehyde of formula (III) R 3 CHO (III) (where R 3 represents hydrogen or lower alkyl to give a hexahYdropyrimidine of formula (IV) CN-R 2 m.,""L R 3 1 H (IV) (where R 2 and R 3 have the meanings given above), acylating the hexahydropyrimidine to give an acylated hexahydropyrimidine of formula (V) 1 H-400-GB nNR 2 1 R 3 --, N --- CO. R (V) (where R 1, R 2 and R 3 have the meanings given above) and hydrolysing the acylated hexahydropyrimidine.

2. A process as claimed in cla3m 1 wherein R is a substituted or unsubstituted alkyl or aryl group.

3. A process as claimed in claim 2 wherein the alkyl or aryl group is substituted by one or more halogen, hydroxy, alkoxy, amino, monoalkylamino, dialkylamino, acylamino, or trifluoromethyl substituents.

4. A process as claimed in any one of claims 1 to 3 in which R 1 represents RNH-

5. A process as claimed in claim 4 wherein R is unsubstituted phenyl or phenyl substituted by one or more of the substituents specified in claim 3.

6. A process as claimed in any one of the preceding claims in which R 2 is lower alkyl.

7. A process as claimed in claim 1 in which R 1 represents RNH where R is 2,6-dimethylphenyl and R 2 is isopropyl.

8. A process as claimed in any one of the preceding claims wherein the reaction product of the diamine and the aldehyde is acylated in situ.

H-400-GB

9. A process as claimed in any one of the preceding claims wherein the hexahydropyrimidine is acylated with an isocyanate, an acyl halide or an acid anhydride.

10. A process as claimed in any one of the preceding claims wherein the reaction product of the acylation product is hydrolysed in situ.

11. A process as claimed in claim 1 substantially as hereinbefore described with reference to Examples 1, 2 and 3.

12. A compound of general formula C-R 2 Nw,' R 3 (Va) CO. NH. R where R, R 2 and R 3 are defined in any one of claims 1 to 3.

13. 1(2,6-Di-m-ethylphenylaminocarbonyl)-3isopropylhexahydropyrimidine.

Published 1991 at Ite Patent Office. State House. 66171 High Holborn. London WC1R47P. Further copies rnay be obtained frornThe Patent Office Branch. St Mary Cray. Orphtgwn. Kent BR5 3RD. Printed by Multiplex techniques ltd. St Mary Cray. Kent Con. 1/87